Project Summary/Abstract Rapid restoration of blood flow of an occluded coronary artery by angioplasty and stenting (PCI) is the most effective therapy for reducing infarct size in ST-segment elevation myocardial infarction (STEMI). However, reperfusion may also be associated with further injury to the myocardium and vasculature that can be as significant as the initial ischemic insult. Despite significant advances in the treatment of STEMI, many patients will still have significant myocardial injury and develop congestive heart failure (CHF), the leading hospital admission diagnosis in this country. Reducing reperfusion injury in the setting of STEMI may significantly improve left-ventricular (LV) function and reduce the development of CHF. However, the development of novel forms of myocardial protection in this setting has been grossly underutilized. Recently, a modified reperfusion technique to reduce reperfusion injury was introduced called postconditioning (PostC). This utilizes a series of brief (30 s) occlusions of the artery followed by reperfusion (30 s) over several cycles which commences immediately upon reperfusion of the occluded artery. This technique was demonstrated to reduce infarct size in dogs by 44% following a 60 minute coronary occlusion. This technique is easily transferred to the setting of primary PCI in patients with STEMI using a PTCA balloon to control reperfusion. Preliminary data from our clinic and several other small clinical trials suggest that PostC may also reduce infarct size in patients. However, there are no long- term studies to examine if the initial benefit on infarct size reduction is maintained beyond the acute period. This proposal describes a single center Phase II, randomized clinical trial in 120 patients with STEMI that will greatly increase our understanding of the effectiveness and mechanisms of PostC. Patients enrolled in this trial will come from our Level 1 Acute MI Program; a nationally recognized regional transfer system involving 36 hospitals in Minnesota. This program treats approximately 500 STEMI patients per year. This protocol will significantly improve upon previous studies by using cardiac MRI to evaluate infarct size, myocardial salvage and degree of microvascular obstruction, which is a strong predictor of adverse LV remodeling. Patients will undergo MRI evaluations at Day 3-5, 3 months and 12 months to ascertain if the initial described benefit of this intervention is sustained over time which is currently not known. We will explore the changes in several cellular markers that will shed light on the mechanisms of benefit of Post C including measurements of nitrite anion (nitric oxide), hydrogen sulfide and reactive oxygen species. The findings that PostC reduces infarct size and improves myocardial salvage that results in sustained improvement in LV function would represent a marked advancement in the treatment of STEMI patients and result in a significant public health benefit. Furthermore, this intervention can be performed at no additional cost to the patient or facility.